With the imminent institution of smallpox vaccination for healthcare workers and first responders, there is an urgent need to better understand the biology of vaccinia infection in humans. In response, we are creating a new Core Facility, the Smallpox Vaccine Clinical Research Center, to coordinate and facilitate clinical/translational research on smallpox for the MRCE. The Smallpox Vaccine Clinical Research Center will serve two allied missions. First, it will be the clinical/translational research arm of the MRCE, facilitating the research designed to answer critical questions about viral shedding, protective immunity, and susceptibility to poxvirus infections (see the Strategic Projects of Storch, Kazura, and Belshe, section C). In this mode it will directly support and execute translational research protocols on projects of special interest to the MRCE mission. The initial protocols will test the efficacy and mechanism of action of vaccinia immune globulin; an additional project is to fully characterize the immunologic responses of a non-responder to vaccinia immunization. Standard research protocols for characterizing individuals with severe adverse effects to smallpox vaccination will also be supported. The Smallpox Vaccine Clinical Research Center will serve its second mission by becoming the regional center for the diagnosis and care of individuals with serious adverse effects after smallpox vaccination. In addition to providing state of the art diagnostics and care, for these individuals, when appropriate, the Smallpox Vaccine Clinical Research Center will offer to enroll them into clinical/translational protocols on the adverse effects of smallpox vaccination. If possible, these individuals will undergo many of the detailed virologic, immunologic, and genetic studies outlined in the projects of Drs. Storch, Kazura, and Belshe. Some of these individuals may have immunodeficiencies (e.g. those with generalized vaccinia or progressive vaccinia) and these will be fully characterized. In this capacity the Smallpox Vaccine Clinical Research Center will also become a database for adverse effects to smallpox vaccine in this area, and facilitate any national efforts in this area.